The mechanism of tumor suppression is an area of intensive research today. Significant efforts are made to utilize tumor suppressor genes, or antioncogenes that may protect a cell from one step on the path to cancer. The loss of these genes may be even more important than proto-oncogene or oncogenes activation for the formation of many kinds of human cancer cells (Weinberg, Robert A 2014). A variety of therapies are attempted. For example immunotherapy, stimulating or helping the immune system to fight cancer, have come into view since 1997, and this continues to be an area of active research (Waldman T. A. 2003). However, the outcome of treatments aiming at suppression of tumor manifestation are highly uncertain.
A large number of antitumor compounds have been synthesized. Various indolyl compounds are suggested to have an anti-tumor effect in WO2013063492, however, no experimental data showing that the compounds have an anticancer effect is given.
It has never been suggested in the art that the catecholaminergic or the serotonergic system would have been linked to any mechanism in the brain effecting tumour manifestation.
It has been recognized for a long time that certain compounds enhance catecholaminergic or serotonergic activity in the brain which may be unrelated to MAO-B inhibition (Knoll and Miklya, 1994).
This enhancer regulation involves the existence of enhancer—sensitive neurons in the brain capable of working in a split-second on a significantly higher activity level. It has been found that an endogenous enhancer substance Phenylethylamine (PEA) enhances the impulse—propagation mediated release of monoaminergic substances, including the catecholamines dopamine and noradrenalaine, and serotonin [see Knoll J (2001) CNS Drug Rev 7:317-345 and Knoll J (2003) Neurochem Res 28:1187-1209]. Enhancer substances may have their own receptors on specific enhancer-sensitive neurons that facilitate the release of neurotransmitters depending on neuronal firing activity.
The enhancer regulation also plays an important role in development of acquired drives, that are important determinants of our lifelong activity and equilibrium. Enhancer regulation of these cortical neurons is required for manifesting acquired drives and reaching our goals. Enhancer regulation affects our learning capacity and regulates our perception through sensory neurons. The optimal activity of these cortical and brainstem neurons relies upon on their endogenous enhancer substances to keep them active and balanced. Having proper and active enhancer activity as we age is essential to a long, fulfilling, active and healthy lifespan [see Knoll J (2003) Neurochem Res 28:1187-1209].
The enhancer compounds are a kind of “neuroampliers”. They enhance the electronic coupling in the synaptic gap junction of linked regions of cells for greater signal strength in the pulses of neurotransmitter release. This effect is related to the increasing the signal-to-noise ratio for stronger signal firing. Thus, by this mechanism the release of monoamine neurotransmitters is more efficiently coupled to the electrical impulse that triggers their release, and the activity of monoaminergic neurons is upregulated resulting in an immediate and strong activity. These finding have been heralded as being of great importance for cognitive enhancement or clinical importance in Parkinson's disease and Alzheimer's disease, where the nigrostriatal tract and mesolimbic-cortical circuits under-function and for effectively treating depression due to an under-activity of both dopamine and noradrenalin neurons [EP1052259B1 corr. to WO 2000/026204, EP 0 957 080 B1 corr. to WO 1999/007667, Knoll J (2001) CNS Drug Rev 7:317-345, Miklya I (2011) InTech Open Acces Publisher (www.intechopen.com), pp. 77-100.]. This catecholaminergic and serotonergic system keep the higher brain centers active and the continuous decline of the mesencephalic enhancer regulation during the post-developmental phase of life is somehow related with age [Knoll J (1994) Pharmacol Toxicol 75:65-72].
A number of compounds which potentially have an enhancer activity have been synthesized and proposed for the treatment of various neurological type disorders.
For example, many ethylamine derivatives have already been disclosed. Certain 6-(2-aminoethyl)-benzoxazolinone derivatives are described as anti-anxiety drugs and drugs for heart failure in EP 110,781. Moreover, aminoalkylbenzoxazinone derivatives are described as useful remedies for damage of central nervous system in FR 2,035,749. Moreover, the psychotropic alkylamines are taught for use in medicaments in JP 06-99,420 (examined publication). Typically these compounds, while are capable of releasing catecholamines from their depos in the central nervous system, in fact easily deliberate an excess amount of catecholamines resulting in side effects as neurotoxicity, just as stimulants.
One of the most prominent compound in this circle is (−)-Deprenyl (Selegiline, Eldepryl, Jumex, Emsam, Zelepar), originally introduced as the first selective inhibitor of B-type monoamino oxidase (MAO). Deprenyl is registered to treat Parkinson's disease, Alzheimer's disease, major depression disease, and is widely used as an anti-aging compound. The group of the present inventor demonstrated previously that (−)-deprenyl in lower doses, devoid of MAO-B inhibitory potency act as a highly specific catecholaminergic activity enhancer substance. It enhances the impulse propagation generated release of the transmitter. It has been demonstrated in earlier longevity studies performed with (−)-deprenyl that due to its enhancer effect rats maintained on lifelong (−)-deprenyl, preserved their learning ability and sexual activity significantly longer, and lived significantly longer than their placebo-treated peers (Knoll and Miklya, 1995).
The age-related decay in the supply of the brain with PEA, due to the progressive increase of MAO-B activity in the aging brain, and dopamine, due to the better than average decline of the dopaminergic neuronal activity during the post-developmental phase of life, are irresistible biochemical lesions of aging. Previous findings that Deprenyl prolongs life were confirmed in rats, mice, hamsters, and dogs (Table 1).
TABLE 1Previous longevity studies and the confirmation of the finding (m—male; f—female)YearSpeciesConfirmationSpecies1988KnollWistar Logan Rats (m)1989Knoll, Dallo, YenWistar Logan Rats (m)1990Milgram et al.Fischer 344 Rats (m)1993Kitani et al.F 344 Rats (m)1994Knoll, Yen, MiklyaWistar Logan Rats (m)Freisleben et al.Mice (m)1996Dallo, KolesWistar Logan Rats (f)Archer et al.Mice (m, f)1997Bickford et al.F344 rats (m)Ruehl et alBeagle dogsStoll et al.Syrian hamsters (f)
It has been shown that from weaning until sexual maturity an increased enhancer regulation operates in the catecholaminergic and serotonergic neurons. This mechanism terminates developmental longevity and constitutes the foundation of the transition from adolescence to adulthood (Knoll et al., 2000).
The enhancer-sensitive catecholaminergic and serotonergic neurons work before weaning at a low, “economic” level, which is dramatically intensified after weaning. The tense excitement remains unchanged during the developmental phase of life, from weaning until sexual maturity. Sexual hormones (estrone, testosterone) return the enhanced catecholaminergic and serotonergic activity to the pre-weaning, “economy” level, terminating the developmental phase of life. This change is also the beginning of the slow, continuous decay of the enhancer regulation (aging) until “natural death”. It is obvious that only the development of a safe and efficient preventive pharmacological intervention, starting immediately after the completion of sexual maturity, can significantly slow brain aging. In the extremely low dose range in which they exert their specific enhancer effect, the enhancer substances selectively transform the lower performing enhancer sensitive neurons into better performing ones.
In retrospection the outcome of the second longevity study, published in 1994, was the first undeniable proof of this mechanism. In a longevity study out of 1600, 28-week-old males of the robust, long-living Wistar-Logan strain of rats, the 94 sexually lowest performing (LP) and 99 sexually highest performing (HP) ones were selected and treated with saline and Deprenyl, respectively, for life. The saline treated LP rats (n=44) lived 134.58±2.29 weeks, and their HP-peers lived 151.24±1.36 weeks (P<0.001). The Deprenyl treated LP rats (n=49) lived significantly longer than their saline treated peers and lived as long as the saline-treated HP rats. Deprenyl treatment also transformed the innate HP rats (n=50) into better performing ones. They lived 185.30±1.96 weeks. Out of the 50 rats, 17 lived longer than the maximum lifespan ever observed during a long observation period on hundreds of untreated or saline treated rats in the strain used in our studies.
The enhancer effect has a bi-modal, double bell-shaped concentration-effect curve wherein one of the effective concentration ranges of the enhancer substance is needed for a good performance. The lower curve is related to the specific enhancer effect whereas the one at higher concentrations to the non-specific effect.
The finding that also tryptamine is a CAE substance like PEA (Knoll 1994) and experimental evidence that the serotonergic neurons work with significantly enhanced activity in the rat brain from weaning until sexual maturity (Knoll and Miklya 1995), clearly indicated that, like PEA, tryptamine is also an endogenous enhancer substance.
The discovery that tryptamine is, like PEA, a natural enhancer substance (Knoll, 1994), initiated the structure-activity-relationship study aiming to develop a new family of synthetic enhancer compounds; unrelated to PEA and the amphetamines. Of the newly synthesized compounds (R)-1-(benzofuran-2-yl)-2-propylamino pentane ((−)-BPAP or BPAP in short), for the time being is known as the most potent and selective one.
A further tryptamine derivative, (R)-(−)-1-(indol-3-yl)-2-propylamino pentane ((−)-IPAP or IPAP in short) the also a potent, tryptamine-derived, selective enhancer substance, which is, similarly to BPAP, a weak MAO-A inhibitor and has no releasing effect.
The development of BPAP (FIG. 2.) exerts its specific enhancer activity even in femto/picomolar concentration (Knoll et al., 1999). Experimental and clinical studies with Deprenyl and BPAP proved that preventive administration of synthetic enhancer substances during post-developmental life significantly slows the aging-related decay of behavioral performances and prolongs life. In humans, maintenance from sexual maturity on Deprenyl is today the only available treatment with a promising chance to reach this aim and afford chance to prevent or delay the onset of aging-related neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease; though BPAP has also been suggested and disclosed as effective in these indications (see e.g. WO1999007667, JP04953040B2 and JP04953041B2).
In WO1999007667 further compounds enhancing catecholamine and serotonine release by CAE or SAE effect, respectively, were disclosed and found useful as psychotropic agents, antidepressants and in the treatment of Parkinson's disease and/or of Alzheimer's disease (JP 9/247445).
Considerable attention has been paid to the activity enhancer effect of monoaminergic neurons, preferably catecholaminergic enhancer effect (CAE) effect of catecholaminergic neurons, which is an action to enhance the catecholamine release due to amplification of the membrane potential dependent exocytosis, and which is different from the above releasing action by displacing catecholamine from their storage [Life Sci., 58, 945-952 (1996), WO1999/007667 and WO2000/026204]. Compounds enhancing catecholamine release by CAE effect were found useful in psychotropic compositions, antidepressants, compositions for the treatment of Parkinson's disease and/or of Alzheimer's disease (WO 1999/007667, also published as EP957080). In WO2000026204 the respective optical isomers from organic amine compounds in WO1999007667 by means of the optical resolution is described. These optically active isomers were found useful remedies by pharmacological screening for the same group of disease, in particular for treating Parkinson's disease, and/or Alzheimer's disease.
BPAP and its pharmacologically acceptable salt is specifically taught and described as useful in particular in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or as a preventive agent of a disease in which apoptosis occurs, in JP04953040B2. In JP04953041B2 this compound is also suggested for use in the treatment or prevention of further neurodegenerative diseases, such as a peripheral neuropathy observed of cerebral-ischemia property diseases, such as neurological diseases, such as a retinal pigment degeneration, glaucoma, and spino-cerebellar degeneration, and a cerebral apoplexy, and diabetes, AIDS, and a toxic disease.
Whereas Deprenyl is preferentially a CAE substance and a very weak enhancer of the serotonergic neurons, BPAP, as taught e.g. in JP04953041B2, is a compound which has both catecholaminergic and serotoninergic activity enhancer effect (i.e. the CAE/SAE effect).
To the best of the present inventors' knowledge, neuronal activity enhancer compounds have not been suggested for use in the prevention or treatment of cancer or tumor.